ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.1777C>T (p.Arg593Trp) (rs886039530)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255573 SCV000322273 pathogenic not provided 2016-08-23 criteria provided, single submitter clinical testing The R593W pathogenic variant in the ATP1A2 gene has been reported previously in a family with hemiplegic migraine (Vanmolkot et al., 2006). Functional studies suggest that the R593W variant impacts the pump function of the ATP1A2 protein (Schack et al., 2012). The R593W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R593W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position predicted to be within the phosphorylation subdomain.
Neurogenetics Laboratory - MEYER,AOU Meyer RCV000417013 SCV000494559 uncertain significance Epileptic encephalopathy 2016-11-16 criteria provided, single submitter clinical testing
Invitae RCV001213736 SCV001385385 pathogenic Familial hemiplegic migraine 2019-09-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 593 of the ATP1A2 protein (p.Arg593Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial hemiplegic migraine (PMID: 16538223). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265407). This variant has been reported to affect ATP1A2 protein function (PMID: 16538223, 22117059). For these reasons, this variant has been classified as Pathogenic.

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